It has become a trend to treat a variety of medical conditions by introducing an implantable medical device partly or completely into the body cavity such as oesophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient.
For example, many treatments of the vascular system entail the introduction of a device such as a stent, catheter, balloon, guide wire, cannula or the like. For instance classical treatments for artherosclerosis include medical therapies with balloon-dilatations optionally involving stent-implantation and coronary bypass surgery. Artherosclerosis is one of the most important causes of death in the Western world. Coronary artherosclerosis is the result of a progressive degeneration of the vessel wall which causes the occlusion of the arteries with different substances including lipids, cholesterol, calcium and different types of cells including smooth muscle cells and platelets. Classical treatments include medical therapies, balloon-dilatations optionally involving stent-implantation and coronary bypass surgery.
Balloon-dilatations or percutaneous transluminal angioplasty (PTA) is being applied more and more and consists of breaking up and/or removing already formed deposits along arterial walls using a balloon attached to a catheter that is introduced to a patient percutaneously and threaded through the arteries to the occluded site, where the balloon is inflated. An important limitation of this technique however is the high risk of re-closing (restenosis) of the treated artery. Thus, balloon-angioplasty does not always lead to a permanently opened artery. Though systemic drug therapy has been developed to reduce this restenosis reaction it has not shown convincing results, mostly because of unwanted side effects in other parts of the body while the concentrations in the blood vessel wall at the site of occlusion were too low to be effective.
In order to prevent the re-closing of the arteries, scaffolding devices called stents have been developed which are introduced into the lumen of the artery to keep them open. Unlike the balloon-catheter, the stent remains in the body as a permanent prosthesis.
Stents coatings have been developed for different purposes. Firstly, in order to reduce allergic or immunological reactions to the stent material, biocompatible polymers have been used to improve the biocompatibility of the stent. A coating substance may also add to the strength of the stent, or make its surface smoother, allowing easier introduction into the vessels.
The use of stents to permanently maintain the opening in the lumen of arterial walls has not completely eliminated the problem of restenosis. Apparently, introduction of the stent itself often causes damage to the inner lining of the vessel wall, inducing a ‘reparatory’ reaction leading to platelet aggregation and the migration of vascular smooth muscle cells into the arterial lumen, where they accumulate and cause occlusion of the vessel. While the accumulated platelets can produce inflammatory mediators, the damaged endothelium recruits monocytes and leukocytes to the injury site, further contributing to neointimal hyperplasia.
The problem of stent-induced restenosis has been addressed in different ways. Irradiation therapy has been suggested based on intravascular low-power red laser light (LPRLL), using a liquid sodium 186Re perrhenate solution as beta emitter, or potentially gamma radioactive stents made of platinum-iridium. Use of radioactive materials in intimate contact with body tissue over long periods is not preferred.
Alternatively, local drug delivery by the stents themselves has been suggested. Bare metallic stents can be used as a platform to deliver drugs locally where the stents struts enter the vascular wall providing a high drug concentration around the stent struts. Though bare stents can be loaded with a drug without using a carrier interface, the amount of drug loaded this way is low and the release curve fast and not controllable (De Scheerder et al. 1996, Coron Artery Dis 7(2):161-166). Most drug eluting stents therefore use a drug carrying interface, e.g. a coating. Coated stents can be loaded with a larger amount of drug and drug release can be better modified to obtain a more optimal drug release profile resulting in more prolonged effective tissue drug levels. Moreover, this form of drug-delivery is not limited to restenosis-inhibiting compounds.
A number of biocompatible materials suitable for the coating of implantable medical devices have been developed. More particularly, in the field of stent-coating several materials have been tested for drug delivery-characteristics either in animal models only or also in clinical trials, such as phosphorylcholine (PC), polylactide or polylactide copolymers and fluorinated polymethacrylates PFM-P75.
More recently elastomeric poly(ester-amide) (coPEA) polymers and poly-bis-trifluorethoxy phosphazene (PTFEP) have been shown to have the required biocompatibility characteristics and have been suggested as a candidate for local drug delivery. Using stacked layers of polymer it was been demonstrated that the pharmacokinetics of the drugs could be manipulated.
Different drugs have been tested using local delivery from stent coatings to reduce neointimal hyperplasia, including anti-proliferative, immunosuppressive, anti-thrombotic and anti-inflammatory drugs. Heparin has shown only limited benefits in clinical trials.
Use of poly(organo)phosphazene coating impregnated with the corticosteroid methylprednisolone was shown to result in a significantly reduced neointimal thickening over the long term (6 weeks) after stenting of pig coronary arteries (De Scheerder et al. 1996, Coronary Artery Disease 7(2):161-166). More recently, local delivery of a high dose of methylprednisolone from phosphatidyl choline-coated stents or PMF 75 spray-coated stents was found to effectively decrease inflammatory response and result in a significant reduction of neointimal hyperplasia.
Other new drugs also appear to be promising. Recent studies have evaluated these drugs as to their release kinetics, effective dosage, safety in clinical practice and benefit. These studies include trials on sirolimus or rapamycin (RAVEL, SIRIUS), Actinomycin D (ACTION), Tacrolimus (PRESENT), Placitaxel and derivatives (SCORE, ASPECT, ELUTE), dexamethason (EMPEROR), everolimus (FUTURE).
Estrogen inhibits intimal proliferation and accelerates endothelial regeneration after angioplasty. 17Beta-estradiol-eluting phosphorylcholine coated stents were found to be associated with reduced neointimal formation. Gene therapy on the vessel wall by local delivery of DNA has also been considered. Effective transfection of neointimal cells was demonstrated using plasmid DNA loaded Polylactic-polyglycolic acid (PLGA) as stent coating.
WO 03/035134 describes a stent coating composition comprising a biodegradable carrier and a bioactive component. The biodegradable carrier is either polymeric or non-polymeric and examples of non-polymeric carriers are vitamin E or derivatives thereof, peanut oil, cotton-seed oil, oleic acid- or combinations thereof.
One of the drawbacks of conventional means of drug delivery using coated medical devices however, is the difficulty in effectively delivering the bioactive agent over a short term (that is, the initial hours and days after insertion of the device) as well as over a long term (the weeks and months after insertion of the device). Another difficulty with the conventional use of stents for drug delivery purposes is providing precise control over the delivery rate of the desired bioactive agents, drug agents or other bioactive material.
In view of the potential drawbacks to conventional drug delivery techniques, there exists a need for a mechanism for controlling the release rate of the drugs for implantable medical devices to increase the efficacy of local drug delivery in treating patients. There is a need for a device, method and method of manufacture which enable a controlled localised delivery of active agents, drug agents or bioactive material to target locations within a body.